The present invention relates to new benzamidine derivatives which can be orally administrated to exhibit a strong anticoagulant effect by reversibly inhibiting activated blood-coagulation factor X; anticoagulants containing them as active ingredients; and agents for preventing or treating diseases caused by thrombi or emboli. These diseases include, for example, cerebrovascular disorders such as cerebral infarction, cerebral stroke, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA) and subarachnoidal hemorrhage (vasospasm); ischemic heart diseases such as acute and chronic myocardial infarction, unstable angina and coronary thrombolysis; pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism; peripheral occlusion; deep vein thrombosis; disseminated intravascular coagulation; thrombus formation after an artificial blood vessel-forming operation or artificial valve substitution; re-occlusion and re-stenosis after a coronary bypass-forming operation; re-occlusion and re-stenosis after reconstructive operation for the blood circulation such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCR); and thrombus formation in the course of the extracorporeal circulation.
As the habit of life is being westernized and people of advanced ages are increasing in Japan, thrombotic and embolismic patients such as those suffering from myocardial infarction, cerebral thrombosis and peripheral thrombosis are increasing in number year by year, and the treatment of patients with these diseases is becoming more and more important in the society. Anticoagulation treatment is included in the internal treatments for the remedy and prevention of thrombosis, like fibrinolytic therapy and antiplatelet therapy.
Thrombin inhibitors were developed as thrombus-formation inhibitors in the prior art. However, it has been known that since thrombin not only controls the activation of fibrinogen to form fibrin, which is the last step of the coagulation reaction, but also deeply relates to the activation and aggregation of blood platelets, the inhibition of the action of thrombin causes a danger of causing hemorrhage. In addition, when thrombin inhibitors are orally administered, the bioavailability thereof is low. At present, no thrombin inhibitors which can be orally administered is available on the market.
Since the activated blood coagulation factor X is positioned at the juncture of an extrinsic coagulation cascade reaction and an intrinsic coagulation cascade reaction and in the upstream of thrombin, it is possible to inhibit the coagulation system more efficiently and specifically, than the thrombin inhibition, by inhibiting the factor X (Tidwell, R.; Webster, W, P.; Shaver, S. R.; Geratz, J. D. THROMBOSIS RESEARCH, Vol. 19, pages 339 to 349; 1980).
Benzamidine derivatives capable of selectively inhibiting activated blood coagulation factor X have been disclosed until now (see, for example, WO 9831661 and WO 9964392). However, it is eagerly demanded to further develop a medicine having a more excellent effect of inhibiting activated blood coagulation factor X and also an excellent effect of inhibiting the blood coagulation.
The object of the present invention is to provide compounds having an excellent effect of inhibiting the effect of activated blood coagulation factor X.
Another object of the present invention is to provide compounds having an effect of specifically inhibiting the effect of activated blood coagulation factor X, which can be orally administered.
Still another object of the present invention is to provide a blood-coagulation inhibitor or an agent for preventing or treating thrombosis or embolism, which contains one of the above-described compounds.
A further object of the present invention is to provide agents, containing one of the above-described compounds, for preventing and treating diseases caused by cerebrovascular disorders, diseases caused by ischemic heart diseases, diseases caused by pulmonary vascular disorders, peripheral embolism, deep vein thrombosis, disseminated intravascular coagulation, thrombus formation after an artificial blood vessel-forming operation or artificial valve substitution, re-occlusion and re-stenosis after a coronary bypass-forming operation, re-occlusion and re-stenosis after reconstructive operation for the blood circulation, and thrombus formation in the course of the extracorporeal circulation.
Another object of the present invention is to provide a pharmaceutical composition containing an above-described compound(s).
After intensive investigations made under these circumstances, the inventors have found that specified new benzamidine derivatives having a phosphonoethyl group have an excellent effect of inhibiting activated blood coagulation factor X and are usable for preventing and treating various diseases caused by thrombi and emboli. The present invention has been completed on the basis of this finding. For example, a compound of formula (2-1) given below has an effect of selectively inhibiting activated blood coagulation factor X. Namely, this compound has an excellent effect of inhibiting activated blood coagulation factor X (pIC50=8.5), while it has no activity of inhibiting thrombin (pIC50= less than 3.5).
In addition, the compound of formula (2-1) also exhibited a high activity of inhibiting the blood coagulation (pPT2=6.8).
Namely, the present invention provides benzamidine derivatives of following general formula (1) or pharmaceutically acceptable salts thereof, and blood coagulation inhibitors containing them as the active ingredients: 
wherein X represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkyl group having 1 to 3 carbon atoms, which may have a substituent(s), or a benzyl group which may have a substituent(s); the substituent(s) being a carboxyl group or alkoxycarbonyl groups having 2 to 8 carbon atoms, and V represents a benzoyl or piperidinecarbonyl group which may have a substituent(s); the substituent(s) being selected from the group consisting of iminoalkylpiperidyloxy groups having 7 to 10 carbon atoms, aryl groups having 6 to 10 carbon atoms, heteroaryl groups having 4 to 5 carbon atoms, carbamoyl group, and mono- and dialkylcarbamoyl groups having 2 to 7 carbon atoms.